耶魯大學等處的科學家研究發(fā)現(xiàn),，當青少年第一次接觸可卡因的時候,，大腦就會發(fā)射出一種強烈的防御反應，來最大程度的降低藥物的效應,；近日,，來自耶魯大學研究小組的兩項最新研究發(fā)現(xiàn)了一個關鍵基因，該基因可以調節(jié)青少年的這種效應,，而且可以劇烈干擾這種效應,，而且增加小鼠對可卡因的敏感性。
這些新的研究發(fā)現(xiàn)可以幫助我們理解,，在青少年時候便開始使用可卡因的人為什么藥物成癮和濫用的風險增加的如此明顯,。這項研究結果將刊登在2月14日和2月21日的國際著名雜志Journal of Neuroscience上。
研究者表示,，可卡因的損害性在青年時期尤為高,，因為青少年時期，大腦正處于可塑性階段,，向著成年人的大腦轉變,，耶魯大學過去的研究表明，第一次接觸可卡因時,，整聯(lián)蛋白因子beta1可以進行調節(jié),，使得神經(jīng)元和突觸聯(lián)接容易改變形狀,，這對于脊椎動物神經(jīng)系統(tǒng)的發(fā)展至關重要。這種結構的改變很有可能是神經(jīng)系統(tǒng)在第一次遇到可卡因時候的一種自我保護措施,，Anthony Koleske教授這樣說,。
在最新的研究中,，耶魯大學的研究者報道了,，他們破壞了該途徑（整聯(lián)蛋白因子beta1調節(jié)途徑）之后發(fā)現(xiàn)，相比正常小鼠,，這些受損小鼠需要近乎3倍的可卡因才能刺激機體做出行為的改變,。研究揭示，個體的整聯(lián)蛋白beta1途徑的相對強度或許可以解釋為什么有些可卡因使用者脫離了那種環(huán)境之后,，可以戒掉對于藥物的成癮性,。
2月14這篇刊登的文章中，研究者是為了尋找一些在防止大腦受可卡因影響和濫用藥物中起重要作用的基因,，而后期這篇文章是為了描述整聯(lián)蛋白因子beta1是如何控制突觸和突觸成熟以及穩(wěn)定的,。（生物谷：T.Shen編譯）
doi:10.1523/JNEUROSCI.2730-11.2012
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Arg Kinase Regulates Prefrontal Dendritic Spine Refinement and Cocaine-Induced Plasticity
Shannon L. Gourley, Anastasia Olevska1, M. Sloan Warren, Jane R. Taylor, and Anthony J. Koleske
Adolescence is characterized by vulnerability to the development of neuropsychiatric disorders including drug addiction, as well as prefrontal cortical refinement that culminates in structural stability in adulthood. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision making and addictive-like behaviors, although intracellular mechanisms are largely unknown. We characterized layer V prefrontal dendritic spine development and refinement in adolescent wild-type mice and mice lacking the cytoskeletal regulatory protein Abl-related gene (Arg) kinase. Relative to hippocampal CA1 pyramidal neurons, which exhibited a nearly linear increase in spine density up to postnatal day 60 (P60), wild-type prefrontal spine density peaked at P31, and then declined by 18% by P56–P60. In contrast, dendritic spines in mice lacking Arg destabilized by P31, leading to a net loss in both structures. Destabilization corresponded temporally to the emergence of exaggerated psychomotor sensitivity to cocaine. Moreover, cocaine reduced dendritic spine density in wild-type orbitofrontal cortex and enlarged remaining spine heads, but arg−/− spines were unresponsive. Local application of Arg or actin polymerization inhibitors exaggerated cocaine sensitization, as did reduced gene dosage of the Arg substrate, p190RhoGAP. Genetic and pharmacological Arg inhibition also retarded instrumental reversal learning and potentiated responding for reward-related cues, providing evidence that Arg regulates both psychomotor sensitization and decision-making processes implicated in addiction. These findings also indicate that structural refinement in the adolescent orbitofrontal cortex mitigates psychostimulant sensitivity and support the emerging perspective that the structural response to cocaine may, at any age, have behaviorally protective consequences.
doi:10.1523/JNEUROSCI.3942-11.2012
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Integrin β1 Signals through Arg to Regulate Postnatal Dendritic Arborization, Synapse Density, and Behavior
M. Sloan Warren1,2,*, William D. Bradley2,*, Shannon L. Gourley2,5, Yu-Chih Lin2, Mark A. Simpson2, Louis F. Reichardt6, Charles A. Greer1,3,4, Jane R. Taylor1,5, and Anthony J. Koleske1,2,4
Integrins are heterodimeric extracellular matrix receptors that are essential for the proper development of the vertebrate nervous system. We report here that selective loss of integrin β1 in excitatory neurons leads to reductions in the size and complexity of hippocampal dendritic arbors, hippocampal synapse loss, impaired hippocampus-dependent learning, and exaggerated psychomotor sensitivity to cocaine in mice. Our biochemical and genetic experiments demonstrate that the intracellular tail of integrin β1 binds directly to Arg kinase and that this interaction stimulates activity of the Arg substrate p190RhoGAP, an inactivator of the RhoA GTPase. Moreover, genetic manipulations that reduce integrin β1 signaling through Arg recapitulate the integrin β1 knock-out phenotype in a gene dose-sensitive manner. Together, these results describe a novel integrin β1–Arg–p190RhoGAP pathway that regulates dendritic arbor size, promotes synapse maintenance, supports proper hippocampal function, and mitigates the behavioral consequences of cocaine exposure.
